Optically pure α-amino acids are an important compound group as a building block for, for example, designing various physiologically active substances and drugs. Recently, it has been frequently reported that, in particular, an α-amino acid having a side chain which natural α-amino acids do not have, and substances containing the same have unique physiological activities. Therefore, a process for conveniently obtaining such an α-amino acid in an optically pure form is desired. Also, peptides and proteins containing α,α-disubstituted α-amino acids in their amino acid sequence, which have a quaternary carbon atom at the α-position, have a more stable higher-order structure and an improved stability against hydrolytic enzymes compared to naturally occurring ones. Therefore, the importance of α,α-disubstituted α-amino acids in drug development has been increasing, and recently, the development of a process for conveniently obtaining an optically active form of α,α-disubstituted α-amino acids is an urgent issue.
As a classic production method of an optically active α-amino acid having an unnatural side chain, methods using diastereoselective alkylation reactions and addition reactions of a chiral glycine enolate equivalent and various electrophiles have been reported. For example, Non-patent Literature 1 discloses a method using a chiral bislactim ether as a chiral glycine equivalent. However, this method needs several steps for synthesis of bislactim ether, as the chiral glycine equivalent. Moreover, a reagent which is expensive and difficult to handle is required for conversion of amide to imidate and an intended amino acid derivative is required to be separated from other amino acid derivatives, such as valine, which are used as a chiral auxiliary. Therefore, the method is difficult to apply to large-scale synthesis. Non-patent Literature 2 discloses a method using imidazolidinone as a chiral glycine equivalent. However, this method needs several steps for synthesis of 2-alkyl-1,3-imidazolidinone, as the chiral glycine equivalent. In addition, the resulting imidazolidinone derivative is an isomeric mixture and therefore, needs to be subjected to separation by chromatography or the like. Moreover, this method needs expensive pivalaldehyde. Therefore, the method is difficult to apply to large-scale synthesis. Non-patent Literature 3 discloses a method using 5,6-diphenylmorpholin-2-one as a chiral glycine equivalent. However, the chiral substance 1,2-diphenyl-2-aminoethanol as a raw material of this method is expensive, and the method needs several steps for synthesis of 5,6-diphenylmorpholin-2-one, as the chiral glycine equivalent. In addition, 1,2-diphenyl-2-aminoethanol, which is used as a chiral auxiliary, is usually removed by a reduction reaction when obtaining an amino acid in the final step, and thus, loses the chirality. Therefore, the chiral auxiliary cannot be recovered. Accordingly, there is a serious problem of cost efficiency also in this method, and the method is difficult to apply to large-scale synthesis. Moreover, in a method disclosed in Non-patent Literature 4, a chiral nickel (II) complex using proline as a chiral source is used as a chiral glycine equivalent, and the Michael reaction thereof is reported. In addition, a large number of applications of the nickel (II) complex to a diastereoselective alkylation reaction, a diastereoselective aldol reaction, and a diastereoselective Mannich reaction are also reported. However, in all the reactions, a chiral center of proline is stereochemically unstable and is prone to epimerization. Therefore, the recovery and recycling of ligands are difficult in this method.
The above four methods are prominent examples of the method using a chiral glycine enolate equivalent for the production of an optically active α-amino acid having an unnatural side chain. However, all the methods have disadvantages that hinder their industrial application on a multi kilogram scale, and the development of a novel method which can eliminate such disadvantages has been demanded.